Bilateral Primary Breast Cancer: A Case Report and Literature Review

Invasive micropapillary carcinoma (IMPC) and secretory carcinoma of the breast (SCB) are relatively rare types of breast cancer. IMPC is usually associated with high incidence of lymphovascular invasion, lymph node metastasis and poor prognosis. While SCB usually carries a relatively favorable prognosis, cases of axillary and distant metastases have been reported. Clinicians generally adopt systemic treatments based on the histopathological ndings of the patients to improve the prognosis, but there is currently no consensus on the optimal treatment for these two types of cancer. of lung adenocarcinoma micropapillary component of breast.


Introduction
Invasive micropapillary carcinoma (IMPC) is a special subtype of invasive ductal carcinoma of the breast (IDC), which accounts for 2-8% of all breast cancers (1). IMPC is commonly encountered in middle-aged and elderly women, and does not differ signi cantly from IDC in terms of the median age of the patients (2)(3)(4)(5). Previous studies have demonstrated that IMPC has a higher propensity for lymph node and vascular invasion, higher local recurrence rate and worse prognosis compared with IDC (2,(4)(5). Due to the relatively low incidence of this disease and its poor prognosis, no consensus has yet been reached regarding the diagnosis, treatment and prognosis evaluation of patients with IMPC. SCB is an extremely rare histological subtype of in ltrating breast malignancy, accounting for < 0.02% of all breast cancers (6). This disease was rst reported in 1966 as a juvenile breast carcinoma occurring in young children (7), but the majority of the cases have since been reported more frequently in adults (8).
Moreover, compared with IDC, although the patients are more likely to be female, rare cases have also been reported in men (6,9,10). Its unique histopathological characteristics suggest that SCB is a low-grade malignant tumor, with a generally slow progression and favorable prognosis, but there is a risk of long-term recurrence (6,9,11).
We herein report a case of primary IMPC of the right breast and concurrent SCB of the left breast occurring in a 50-year-old female patient. Furthermore, in order to further improve our understanding of these two types of breast cancer, the related literatures with clinical cases was reviewed, and their clinical characteristics, diagnosis and treatment were discussed.

\ Case Presentation
A 50-year-old woman without family history of breast cancer visited Zhejiang Provincial Hospital of TCM in September 2019 for treatment due to bilateral breast lumps found on her recent routine health check.
The patient underwent video-assisted thoracosopic surgery for left lung cancer at Shanghai Ruijin Hospital in January 2019. The pathological results indicated left lung adenocarcinoma centered on micropapillary-type.
On physical examination, a super cial, smooth mass was detected in the inner quadrant of the left breast, measuring ~ 1.5 cm. There was no palpable mass in the right breast or enlarged axillary lymph nodes. Breast ultrasonography revealed an irregularly shaped mass of the right breast (Fig. 1A), with blurry borders and multiple ne, strongly echogenic dots inside, as well as an oval-shaped, hypoechoic mass with clear and smooth borders in the left breast (Fig. 1B). Magnetic resonance imaging (MRI) examination of the right breast ( Fig. 2A) demonstrated an upper-quadrant, irregularly shaped lesion exhibiting restricted diffusion, heterogeneous internal enhancement con guration, with a time-signal curve of the plateau type, while the regular, round lump in the left breast ( Fig. 2B) exhibited unrestricted diffusion, internal irregular rim enhancement, with a time-signal curve of the mild-washout type. The comprehensive assessment results of breast imaging reporting and date system (BI-RADS) classi cation method were de ned as BI-RADS 5 and BI-RADS 4. Thus, based on the ndings of the clinical examination mentioned above, the right tumor was initially diagnosed as malignant and the left one as a non-aggressive tumor.
Wide local excision and right sentinel lymph node biopsy (SLNB) were performed, and the fast-frozen pathological examination of resected specimens revealed invasive carcinoma of the right breast and an ill-de ned tumor of the left breast. After 1 week, however, the conventional histopathological examination diagnosed the right tumor as IMPC (Fig. 3) and the left tumor as SCB (Fig. 4). On immunohistochemical staining, the cells of the right tumor were positive for human epidermal growth factor receptor 2 (HER-2) and negative for estrogen receptor (ER). In addition, a micrometastasis was detected in the sentinel lymph node (Fig. 5). The cells of the left tumor were found to be positive for S-100 and ER, and negative for HER-2. In view of the existence of ductal carcinoma in situ component in the right tumor, we do not consider it to be a lung metastasis. The patient was called in and left SLNB was performed.
The overall postoperative course was uneventful and the patient was discharged on postoperative day 5.
The patient has completed adjuvant chemotherapy with EC-T (four cycles of cyclophosphamide and epirubicin, followed by four cycles of docetaxel) and adjuvant radiation therapy after chemotherapy completion. Follow-up examination at one year postop showed no evidence of recurrence by physical exam or ultrasound.

Discussion
IMPC of the breast was de ned by the World Health Organization in 2012 as a morphologically distinct form of mammary carcinoma consisting of small, hollow, and morula-like tumor cells, characterized by reversed polarity of the tumor cells and a space between the cancer cells and the stroma (12).
As mentioned in a number of case reports, IMPC and common invasive breast cancer appear to have no signi cant differences in terms imaging characteristics, and they are di cult to distinguish based on clinical presentation and imaging ndings alone. Yoon et al (3) conducted a study including 308 matching cases of IMPC and IDC, and found that the IMPC group had more angular or indistinct lesion margins, while in the IDC group the margins appeared more spiculated. Imaging examination is only an auxiliary examination method without characteristic ndings. The nal diagnosis is based on pathological examination, which is deemed to be the gold standard.
Compared with IDC, IMPC displays a more distinctive architecture. It is composed of small, hollow or morula-like clusters of cancer cells, surrounded by clear stromal spaces. The neoplastic cells characteristically display a reverse polarity, also referred to as an 'inside-out' growth pattern, whereby the apical pole of the cells faces the stroma rather than the luminal surface (5). There is yet no consensus on the percentage of micropapillary architecture in a tumor required for a diagnosis of IMPC. Yang et al (5) considered that, for an IDC to be classi ed as pure IMPC, the micropapillary component should comprise at least 75% of the tumor. Pure IMPCs are rarely seen, and most tumors are mixed with other types. Chen et al (4) and Ide et al (13) observed that the tendency towards recurrence and metastasis is not associated with the proportion of the IMPC component, as the frequencies of lymphovascular invasion (LVI) and lymph node metastasis (LNM) in breast cancer with a minimal IMPC component were signi cantly higher compared with those without an IMPC component. Furthermore, the incidence of LVI and LNM in breast cancer with a high proportion of IMPC resemble that in tumors with a low proportion.
These ndings indicate that the presence of an IMPC component per se is a crucial factor affecting prognosis, rather than the extent. Therefore, even minor IMPC-like structures should be evaluated accurately during pathological examination and used to guide clinical treatment.
Tumors containing an IMPC component tend to present with a larger size, higher TNM stage and earlier LVI (2,(4)(5)14). Extensive axillary lymph node involvement may be found in most breast cancer patients at the rst clinical visit. In the present case, although the maximum diameter of the right tumor was only 1 cm, the micrometastasis in the sentinel node identi ed on pathological examination constitutes evidence supporting the point mentioned above. In addition, an IMPC case encountered recently as an outpatient had already received surgical treatment, with con rmed involvement of eight lymph nodes. Ye et al (15) analyzed 1,407 patients with IMPC and concluded that larger lesions, younger age at diagnosis, and lack of hormone receptor expression were signi cantly associated with regional nodal involvement.
At present, standard IDC treatment is employed to treat IMPC. Due to the higher risk of LNM and recurrence in patients with IMPC, treatment should include wide surgical margins and adequate lymph node dissection, and conventional radiation therapy is considered to improve postoperative outcomes (16). Several prior studies (14)(15)(16)(17) reported the high rate of positivity of IMPC to ER, progesterone receptor (PR) and HER-2, which may indicate effectiveness of active endocrine therapy. Chen et al (4) reviewed 100 cases of invasive breast carcinoma with an IMPC component. Statistical analysis con rmed the positive effect of tamoxifen endocrine therapy and chemotherapy, while neoadjuvant chemotherapy did not improve the survival rate in patients who received both preoperative and postoperative chemotherapy compared with patients who only received postoperative adjuvant chemotherapy. Yu et al (18) reported a greater degree of locoregional recurrence in the axilla and supraclavicular areas in a matched case-control study, stressing that axillary and supraclavicular radiation therapy should be considered in IMPC patients with axillary node metastasis. In the present case, the immunohistochemical staining results of the IMPC lesion revealed no indication for endocrine therapy; thus, active chemotherapy and targeted therapy were recommended for our patient.
As the number of published reports is limited, there is yet no consensus with regard to the prognosis assessment of IMPC. In 2008, Chen et al (4) found that tumor size, proportion of the IMPC component, histological grade and LNM were not signi cantly correlated with survival rate, but the follow-up results demonstrated poorer 5-year and 10-year survival rates compared with IDC not otherwise speci ed. In 2014, based on the largest retrospective analysis (19) of 636 IMPC and 297,735 IDC cases, IMPC had favorable disease-speci c survival and overall survival (OS) compared with IDC, and the authors reported that ER positivity may a major contributor to the survival advantage. Yu et al (20) in 2015 reported the largest comparative study of IMPC and IDC adopting a counter-factual model. The 5-year and 10-year OS rates did not differ signi cantly, but the locoregional relapse-free survival rate exhibited a notable difference, particularly after 2 years. A 12-year prospective clinical study (21) proposed that accurate pathological diagnosis and individualized treatment may improve the disease-free survival and OS of patients with IMPC.
In summary, as a special type of IDCs, IMPC displays a propensity for aggressiveness and is generally considered as a worse prognostic indicator, and annual breast cancer screening and targeted treatments are deemed necessary. With the increased awareness for IMPC, early detection and treatment can signi cantly improve patient survival.
The 2012 WHO Classi cation of Tumors of the Breast de ned SCB as a rare, low-grade translocationassociated invasive carcinoma (12). Imaging examinations as individual tests have high rates of misdiagnosis, as SBC may mimic benign breast tumors on mammography and ultrasound images (11,22). This makes it di cult to distinguish SCB from other types of breast cancer, or even broadenoma. In the present case, ultrasound examination revealed a mass of the left breast with an oval shape and smooth borders, while the MRI demonstrated unrestricted diffusion. Based on the ndings mentioned above and physical examination, the initial diagnosis leaned towards a broadenoma.
The nal diagnosis of SCB depends on histology, immunohistochemistry and cytogenetics. Microscopically, all specimens display distinct pathological characteristics and abundant secretory material positive for Periodic acid-Schiff stain inside or outside the cancer cells. The tumors are usually positive for p53 and carcinoembryonic antigen, and strongly positive for S-100 (22)(23). In 2002, Tognon et al (24) rst reported that SCB was characterized by expression of the t(12;15)-associated ETV6-NTRK3 fusion gene. This fusion gene would encode a chimeric tyrosine kinase with potent transforming activity in broblasts. This mechanism was later con rmed by other researchers (21,25,26). SCB has been found to be negative for ER and PR, with absence or presence of HER-2 ampli cation, displaying an immunophenotype similar to that of triple-negative breast cancer (27). However, unlike most statistical analyses of clinicopathological results, higher positivity rates of ER and PR are frequently found over recent years (24). A majority of SCBs present a low proliferation index, lacking increased Ki-67 expression. The relatively low value of the Ki-67 index suggests that this is an indolent malignant tumor.
As SCB is one of the rarest types of breast cancer, no comprehensive treatment plan has yet been agreed upon. It is commonly believed that the primary treatment of SCB should be surgical excision, while there is no consensus regarding the extent of surgery. At an early stage, some experts consider mastectomy plus axillary lymph node dissection as the preferred surgical procedure for SCB. The application of breast-conserving surgery and SLNB has been increasingly advocated by clinicians in recent years, particularly for prepubescent women. Ozguroglu et al (28) reviewed 121 cases of SBC, of which 61 underwent surgery, including 20 cases of modi ed radical mastectomy, 12 cases of radical mastectomy, 17 cases of mastectomy and 12 cases of wide local excision, and demonstrated that the results of wide local excision did not differ signi cantly from those of other surgical procedures. Shui et al (29) suggested that, if the size of the primary tumor is < 2 cm, axillary metastasis is uncommon. Li et al (21) believed that breast-conserving surgery and SLNB can only be performed on those patients whose primary tumors are sized < 2 cm and have no axillary LMN. Therefore, we recommend mastectomy or modi ed radical mastectomy for patients with tumors larger than 2 cm in diameter, and consider aggressive SLNB to be crucial.
Due to the rarity of SCB, the e cacy of neoadjuvant chemotherapy, adjuvant chemotherapy and postoperative radiotherapy has not been con rmed by enough clinical studies to date. Soyar et al (30) suggested that patients with primary tumors > 2 cm in diameter should receive axillary lymph node dissection, combined with radiation therapy and chemotherapy. Although previous studies have reported non-response of SCB to chemotherapy (31), in a case report published in 2015, a 13-year-old male patient diagnosed with SCB with metastasis to a single lymph node received chemotherapy with adriamycin and cyclophosphamide for 6 cycles after radical mastectomy, and he has remained disease-free over a 10year follow-up. ER and PR are negative in most cases of SCB, so there is currently no report on the e cacy of endocrine therapy.
As a low-grade carcinoma, SCB has an indolent course and good long-term survival. The prognosis is generally considered to be better in children and adolescents, relatively poor in adults, and distant metastasis is rarely observed (32,33). Axillary lymph node involvement has been reported in 30% of the cases (33), particularly those with primary tumors > 2 cm in diameter. The number of axillary metastatic lymph nodes is generally < 3, whereas > 3 positive lymph nodes may indicate risk of distant metastasis and poor prognosis (34). Local recurrence and distant metastasis have been reported 12, 16 and 20 years after routine surgical treatment; thus, we recommend extending follow-up even up to 20 years (29,31,35,36).
In conclusion, both IMPC and SCB are uncommon types of breast cancer. In the case presented herein, the ndings on the right side indicate a tumor with an unfavorable outcome, with a sentinel lymph node micrometastasis identi ed at an early stage, while the ndings on the left side indicate an inert tumor with good prognosis, although long-term recurrence cannot be ruled out.
With accurate diagnosis based on histopathological examination of the tumors, active individualized therapies and more rigorous management may help improve the prognosis of patients and long-term survival rates. Routine adjuvant chemotherapy after breast-conserving surgery is commonly adopted, while there are not enough studies on the selection of chemotherapy regimens for IMPC and SCB, or the effects of different regimens on prognosis. Related reports on radiotherapy are also sparse. As the special mechanism of balanced translocation t(12;15) and ETV6-NTRK3 gene fusion is characteristic in SCB, we aim to further explore the tyrosine kinase inhibitor in future studies.